Correspondence

Hepatitis C Virus, Human Herpesvirus 8, and the Development of Plasma-Cell Leukemia

N Engl J Med 2003; 348:178-179January 9, 2003

Article

To the Editor:

The role of hepatitis C virus (HCV) and human herpesvirus 8 (HHV-8), two B-cell–tropic viruses, in B-cell proliferation1 is illustrated by the following unusual case of plasma-cell leukemia. In 1995, a 32-year-old man with a history of hepatitis A virus and HCV infection but who tested negative for hepatitis B virus and human immunodeficiency virus was admitted to the hospital with septic shock, bilateral pneumonia, and hepatosplenomegaly. The hemoglobin level was 8.9 g per deciliter; the white-cell count was 26.6×10⁹ per liter with 50 percent plasmablasts (Figure 1AFigure 1Studies in a Patient with Plasma-Cell Leukemia.), 41 percent neutrophils, 7 percent lymphocytes, and 2 percent monocytes; the platelet count was 99×10⁹ per liter. The bone marrow contained 47 percent plasmablasts. The protein level was 57 g per liter, with 15.5 g per liter of gamma globulins and a monoclonal IgG kappa in serum and urine. Antibiotics and chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) were administered, but the patient, who had severe thrombopenia, died of a brain hemorrhage on day 15.

All plasmablasts were CD38+CD138+CD56– CD28– and positive for IgG kappa. They were also CD19+CD45+++, a phenotype usually found in reactive plasma-cell proliferations. However, cytogenetic and fluorescence in situ hybridization analysis confirmed monoclonality and revealed an isolated t(9;14)(p13;q32) translocation, which fused the PAX-5 and IgH genes. This translocation occurs in cases of lymphoplasmacytoid lymphoma, one third of which are associated with HCV2,3 and was reported in tumor cells of an HCV-positive patient with primary-effusion lymphoma, a condition associated with HHV-8.4

Retrospective studies were consistent with an HCV-driven process leading to plasma-cell leukemia. Immunoblotting showed that the monoclonal IgG kappa was directed against HCV core protein (Figure 1B). The patient had HCV viremia (type 1a) and HHV-8 viremia (subtype C'). Reverse-transcriptase polymerase-chain-reaction (PCR) and immunofluorescence studies revealed that his plasmablasts were infected by HCV and produced HCV core protein (Figure 1C). Immunofluorescence and real-time (TaqMan) quantitative PCR studies indicated that 100 percent of plasmablasts were productively infected by HHV-8 (≥300 viral copies per blast) (Figure 1D).

In our patient, HCV and HHV-8 may have acted synergistically to cause plasma-cell leukemia, through the following sequence of events: HCV core – driven oligoclonal expansion of B lymphocytes; HCV infection of an HCV core – specific B-cell clone and monoclonal expansion of the core-specific, core-producing clone; monoclonal-plasmablast expansion after blockade of plasmacytic differentiation due to a PAX-5 rearrangement; and accelerated plasmablast expansion after infection by HHV-8 or reactivation of latent HHV-8 infection. Since patients may benefit from antiviral therapy,5 we propose that in cases of unusual presentation of B-lineage disease, the presence of B-cell–tropic transforming viruses should be investigated.

Sylvie Hermouet, M.D., Ph.D.
Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France
sylvie.hermouet@nantes.inserm.fr

Isabelle Corre, Ph.D.
INSERM Unité 463, 44093 Nantes, France

Michelle Gassin, M.D.
Edith Bigot-Corbel, Ph.D.
Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France

Claudia A. Sutton, Ph.D.
James W. Casey, Ph.D.
Cornell University, Ithaca, NY 14853

5 References

1. 1

   Pagano JS. Viruses and lymphomas. N Engl J Med 2002;347:78-79
   Full Text | Web of Science | Medline

2. 2

   Iida S, Rao PH, Nallasivam P, et al. The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Blood 1996;88:4110-4117
   Web of Science | Medline

3. 3

   Silvestri F, Barillari G, Fanin R, et al. Impact of hepatitis C virus infection on clinical features, quality of life and survival of patients with lymphoplasmacytoid lymphoma/immunocytoma. Ann Oncol 1998;9:499-504
   CrossRef | Web of Science | Medline

4. 4

   Ichinohasama R, Miura I, Kobayashi N, et al. Herpesvirus type 8-negative primary effusion lymphoma associated with PAX-5 gene rearrangement and hepatitis C virus: a case report and review of the literature. Am J Surg Pathol 1998;22:1528-1527
   CrossRef | Web of Science | Medline

5. 5

   Hermine O, Lefrere F, Bronowicki J-P, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347:89-94
   Full Text | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   E. Bigot-Corbel, M. Gassin, I. Corre, D. Le Carrer, O. Delaroche, S. Hermouet. (2008) Hepatitis C virus (HCV) infection, monoclonal immunoglobulin specific for HCV core protein, and plasma-cell malignancy. Blood 112:10, 4357-4358
   CrossRef

2. 2

   James R Cook, Nadine Ives Aguilera, Shalini Reshmi-Skarja, Xin Huang, Zhisheng Yu, Susanne M Gollin, Susan L Abbondanzo, Steven H Swerdlow. (2004) Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: reassessing the reported association with t(9;14)1 1These studies were performed in the University of Pittsburgh Cancer Institute Cytogenetics Facility.. Human Pathology 35:4, 447-454
   CrossRef